WO2020026926A1 - Seringue pré-remplie et procédé de production de seringue pré-remplie - Google Patents

Seringue pré-remplie et procédé de production de seringue pré-remplie Download PDF

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Publication number
WO2020026926A1
WO2020026926A1 PCT/JP2019/029092 JP2019029092W WO2020026926A1 WO 2020026926 A1 WO2020026926 A1 WO 2020026926A1 JP 2019029092 W JP2019029092 W JP 2019029092W WO 2020026926 A1 WO2020026926 A1 WO 2020026926A1
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Prior art keywords
outer cylinder
protein solution
prefilled syringe
solution preparation
gasket
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PCT/JP2019/029092
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English (en)
Japanese (ja)
Inventor
澤口　太一
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日本ゼオン株式会社
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Application filed by 日本ゼオン株式会社 filed Critical 日本ゼオン株式会社
Priority to US17/261,568 priority Critical patent/US20210260297A1/en
Priority to EP19844828.4A priority patent/EP3831429A4/fr
Priority to CN201980048561.XA priority patent/CN112469456B/zh
Priority to JP2020533462A priority patent/JP7484715B2/ja
Publication of WO2020026926A1 publication Critical patent/WO2020026926A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M2005/3103—Leak prevention means for distal end of syringes, i.e. syringe end for mounting a needle
    • A61M2005/3104—Caps for syringes without needle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels
    • A61M2005/3132—Syringe barrels having flow passages for injection agents at the distal end of the barrel to bypass a sealing stopper after its displacement to this end due to internal pressure increase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2207/00—Methods of manufacture, assembly or production
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention relates to a prefilled syringe and a method for producing the prefilled syringe.
  • the injection solution to be filled in the prefilled syringe for example, a preparation containing a protein in an aqueous solution (protein solution preparation) is used.
  • protein solution preparation a preparation containing a protein in an aqueous solution
  • the protein aggregates when stored for a long time.
  • a nonionic surfactant and an isotonic agent are contained in a protein solution formulation containing erythropoietin as a protein while keeping the protein concentration within a predetermined range.
  • the material of the portion that is in direct contact with the preparation is 1) a cycloolefin copolymer which is a copolymer of a cyclic olefin and an olefin, 2) a cycloolefin ring-opening polymer, 3)
  • a container which is a hydrophobic resin selected from hydrogenated cycloolefin ring-opened polymers for example, polysorbate 80 and polysorbate 20 are used as nonionic surfactants. This nonionic surfactant can function as a stabilizer for the protein erythropoietin.
  • nonionic surfactants such as polysorbate 80 and polysorbate 20 are caused by degradation products generated by the decomposition of the nonionic surfactant, but when administered to the human body, It is noted that there are disadvantages such as the possibility of causing problems such as hypersensitivity and chromosomal abnormalities and carcinogenicity. Then, the present inventor tried to lower the concentration of the nonionic surfactant in the protein solution formulation when producing the prefilled syringe using the above-mentioned conventional technology.
  • an object of the present invention is to provide a pre-filled syringe that can suppress aggregation of a protein after long-term storage even when a protein solution preparation having a low concentration of a nonionic surfactant is filled. Further, the present invention provides a method for producing a prefilled syringe capable of suppressing protein aggregation after long-term storage, even when a protein solution preparation having a low concentration of a nonionic surfactant is filled. Aim.
  • the present inventors have conducted intensive studies with the aim of solving the above problems.
  • the present inventor paid attention to the material of the outer cylinder of the prefilled syringe that is in contact with the filled protein solution preparation, and also paid attention to the surface properties of the inner wall surface where the inner wall of the outer cylinder is in contact with the protein solution preparation.
  • the nonionic surfactant in the protein solution preparation is It has been found that even if the concentration of is extremely reduced, it is possible to make it difficult to cause protein aggregation after long-term storage, and thus completed the present invention.
  • an object of the present invention is to advantageously solve the above-described problems, and a prefilled syringe of the present invention includes an outer cylinder having a nozzle portion at a distal end portion, and a sealing member for sealing the nozzle portion.
  • a gasket slidably housed in the outer cylinder, a pusher coupled to the gasket and operating to move the gasket in a longitudinal direction of the outer cylinder, and a part of an inner wall surface of the outer cylinder.
  • the prefilled syringe provided with the outer cylinder having a water contact angle of 90 ° or more in a part of the region (hereinafter sometimes referred to as “formulation contact region”), the prefilled syringe may be stored for a long time.
  • the “water contact angle” of the preparation contact region can be measured by using the method described in the examples of the present specification.
  • the protein solution preparation can contain at least one of an antibody and an antigen-binding fragment thereof.
  • the antibody may be at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody thereof.
  • the protein solution preparation is preferably ofofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumab, denosumumab, denosumumab, denosumumab, denosumumab, denosumumab It may include at least one selected from the group consisting of vercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol, and palivizumab.
  • an object of the present invention is to advantageously solve the above-described problem, and a method of manufacturing a prefilled syringe of the present invention seals an outer cylinder having a nozzle portion at a distal end portion and the nozzle portion.
  • a protein solution is provided inside a syringe including a sealing member, a gasket slidably housed in the outer cylinder, and a pusher connected to the gasket to move the gasket in a longitudinal direction of the outer cylinder.
  • a method for producing a prefilled syringe filled with a preparation comprising: a resin containing at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin; A protein having a non-ionic surfactant concentration of 0 mg / mL or more and 0.01 mg / mL or less in an outer cylinder having a region where a water contact angle is 90 ° or more Injecting a liquid preparation, a step of obtaining a pre-filled syringe filled with the protein solution preparation in the partial area of the inner wall surface of the outer cylinder, the sealing member, and a space defined by the gasket, It is characterized by having.
  • the protein solution preparation is composed of the resin described above, and By filling a syringe provided with an outer cylinder having a water contact angle of 90 ° or more in the contact region, a prefilled syringe capable of suppressing aggregation of proteins in a protein solution preparation can be obtained even when stored for a long time. .
  • the method for producing a prefilled syringe of the present invention prior to the step of obtaining the prefilled syringe, further, a step of pre-drying the resin, and molding the resin after the pre-drying to obtain the outer cylinder
  • the method includes a step.
  • an outer cylinder obtained by molding a pre-dried resin is used, aggregation of proteins in a protein solution preparation can be sufficiently suppressed when the obtained prefilled syringe is stored for a long time.
  • the oxygen concentration in the resin after the preliminary drying is 10 ppm by mass or less.
  • the oxygen concentration in the pre-dried resin is 10 mass ppm or less, the aggregation of the protein in the protein solution preparation can be more sufficiently suppressed when the obtained prefilled syringe is stored for a long time.
  • the “oxygen concentration” in the resin can be measured by using the method described in the examples of the present specification.
  • the preliminary drying is performed in an inert gas atmosphere. If the predrying of the resin is performed in an inert gas atmosphere, the aggregation of the protein in the protein solution preparation can be more sufficiently suppressed when the obtained prefilled syringe is stored for a long period of time.
  • the drying temperature of the preliminary drying is from 80 ° C to 120 ° C. If the pre-drying of the resin is performed at a temperature within the above-mentioned range, the aggregation of the protein in the protein solution preparation can be more sufficiently suppressed when the obtained prefilled syringe is stored for a long time.
  • the protein solution preparation can contain at least one of an antibody and an antigen-binding fragment thereof.
  • the antibody may be at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody thereof.
  • the protein solution preparation is ofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumabumamu, adalimumabumamu, gum It may include at least one selected from the group consisting of infliximab, aflibercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol, and palivizumab.
  • a prefilled syringe capable of suppressing protein aggregation after long-term storage even when a protein solution preparation having a low concentration of a nonionic surfactant is filled. Further, according to the present invention, there is provided a method for producing a prefilled syringe capable of suppressing protein aggregation after long-term storage, even when a protein solution preparation having a low concentration of a nonionic surfactant is filled. be able to.
  • the prefilled syringe of the present invention is obtained by filling a syringe with a protein solution preparation.
  • the prefilled syringe of the present invention can be manufactured, for example, by using the method for manufacturing a prefilled syringe of the present invention.
  • the prefilled syringe of the present invention is an outer cylinder having a nozzle at the tip, a sealing member for sealing the nozzle, a gasket slidably housed in the outer cylinder, and a gasket connected to the gasket.
  • a pusher that moves in the longitudinal direction of the outer cylinder is provided, and the protein solution formulation is filled in the space defined by the formulation contact area, which is a part of the inner wall surface of the outer cylinder, the sealing member, and the gasket. I have.
  • the prefilled syringe 1 shown in FIG. 1 includes an outer cylinder 10, a sealing member (cap in FIG. 1) 20, a gasket 30, a pusher 40, and a protein solution preparation 50.
  • the outer cylinder 10 has a nozzle portion 12 at a distal end portion 11, and a sealing member 20 is fitted to the nozzle portion 12.
  • the gasket 30 can slide inside the outer cylinder 10 in the longitudinal direction of the outer cylinder 10, and the sliding of the gasket 30 can be performed by a pusher 40 connected to the gasket 30.
  • the protein solution preparation 50 is filled in a space defined by the preparation contact area 14 which is a part of the inner wall surface 13 of the outer cylinder 10, the sealing member 20, and the gasket 30.
  • the concentration of the nonionic surfactant in the filled protein solution preparation is 0 mg / mL or more and 0.01 mg / mL or less
  • the outer cylinder is a ring-opened cyclic olefin.
  • a resin containing at least one of a polymer hydrogenated product and / or a copolymer of a cyclic olefin and a chain olefin is formed, and the water contact angle of the formulation contact region of the outer cylinder is 90 ° or more.
  • the prefilled syringe of the present invention uses a molded article of the above-described resin as the outer cylinder, and the outer cylinder has a water contact angle of 90 ° or more in a region where the outer cylinder comes into contact with the protein solution preparation. Even if the concentration of the nonionic surfactant is 0 mg / mL or more and 0.01 mg / mL or less, aggregation of the protein after long-term storage can be suppressed. The reason why such an effect is obtained is not clear, but is presumed to be as follows.
  • protein aggregation in the prefilled syringe occurs when the protein is adsorbed on the inner wall surface of the outer cylinder of the prefilled syringe and the adsorbed protein is collected.
  • the outer cylinder is formed of a hydrogenated cyclic olefin ring-opening polymer and / or a copolymer of a cyclic olefin and a chain olefin, and the water contact angle of the inner wall of the outer cylinder is 90 ° or more
  • the affinity between the formulation contact region of the outer cylinder and the protein can be reduced, and protein adsorption can be prevented.
  • the aggregation of the protein inside the prefilled syringe can be suppressed.
  • the protein solution preparation contains at least a protein and water, and the concentration of the nonionic surfactant is 0 mg / mL or more and 0.01 mg / mL or less.
  • the protein contained in the protein solution preparation is not particularly limited, and includes, for example, antibodies (chimeric antibodies, human antibodies, humanized antibodies, and their domain antibodies), and antigen-binding fragments thereof.
  • the protein solution preparation may contain one kind of protein, or may contain two or more kinds of proteins. That is, the protein solution preparation may contain, for example, both an antibody and an antigen-binding fragment, may contain two or more kinds of antibodies, or may contain two or more kinds of antigen-binding fragments. .
  • the concentration of the protein in the protein solution preparation is preferably at least 0.005 mg / mL, more preferably at least 0.01 mg / mL, even more preferably at least 0.05 mg / mL. , 500 mg / mL or less, more preferably 300 mg / mL or less, even more preferably 200 mg / mL or less.
  • concentration of the protein in the protein solution preparation is 0.005 mg / mL or more, the desired effect of the protein can be sufficiently obtained when the protein solution preparation is administered to a human body or the like. If it is, when the prefilled syringe is stored for a long time, aggregation of the protein in the protein solution preparation can be sufficiently suppressed.
  • Nonionic surfactant arbitrarily included in the protein solution preparation is a component that stabilizes the above-described protein and can function as a stabilizer.
  • a nonionic surfactant is not particularly limited, and examples thereof include sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan oleate (polysorbate 80) and monolaurin).
  • Acid polyoxyethylene sorbitan (polysorbate 20), polyoxyethylene sorbite fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene Alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene beeswax derivative, polyoxyethylene Lanolin derivatives, polyoxyethylene fatty acid amides.
  • a nonionic surfactant may be used individually by 1 type, and may be used in combination of 2 or more type.
  • a protein solution in which the concentration of the nonionic surfactant is 0 mg / mL or more and 0.01 mg / mL or less Use the formulation.
  • non-ionic surfactants having a polyoxyethylene chain polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene Ethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene beeswax derivative, polyoxyethylene lanolin derivative, polyoxyethylene fatty acid amide, etc. Ethylene chain ends can be cleaved by autoxidation to produce degradation products.
  • the concentration of the nonionic surfactant in the protein solution preparation is 0 mg / mL or more and 0.01 mg / mL or less, even if a decomposition product is produced, the amount Is small, and the above-mentioned risks such as hypersensitivity, chromosomal abnormality and carcinogenicity can be sufficiently reduced.
  • the concentration of the nonionic surfactant in the protein solution preparation is preferably 0.005 mg / mL or less, and is preferably 0 mg / mL (lower than the detection limit). More preferred.
  • the protein solution preparation may contain components (other components) other than the protein, water, and the nonionic surfactant.
  • Other components optionally included in the protein solution formulation include known components used in preparing protein solution formulations. Such known components include, for example, stabilizers (excluding the nonionic surfactants described above), diluents, dissolution aids, isotonic agents, excipients, pH adjusters, soothing agents , Buffers, sulfur-containing reducing agents, antioxidants and the like.
  • other components include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium hydrogen carbonate; and organic salts such as sodium citrate, potassium citrate, and sodium acetate.
  • concentration of the inorganic salt in the protein solution preparation is preferably 300 mM or less.
  • the concentration of the organic salt in the protein solution preparation is preferably 300 mM or less.
  • the method for preparing the protein solution preparation is not particularly limited as long as at least the protein is dissolved and the concentration of the nonionic surfactant can be obtained in a predetermined range.
  • it can be obtained by dissolving a protein and a surfactant used as needed in an aqueous buffer such as an acetate buffer, a phosphate buffer, and a citrate buffer.
  • the pH of the obtained protein solution preparation is not particularly limited, but may be 3.0 or more and 8.0 or less.
  • the outer cylinder provided in the prefilled syringe of the present invention is a member having a nozzle at the tip and capable of storing a protein solution preparation and a gasket inside.
  • the outer cylinder 10 includes an outer cylinder main body 15, a nozzle 12 provided on a distal end side (a distal end 11) of the outer cylinder main body 15, and an outer cylinder main body 15. And a flange 16 provided on the rear end side.
  • the outer cylinder main body 15 is a cylindrical portion that houses the gasket 30 in a liquid-tight and slidable manner.
  • the nozzle portion 12 is a cylindrical portion having a smaller diameter than the outer cylinder main body 15.
  • the nozzle unit 12 has an opening at the tip for discharging the protein solution preparation 50 in the outer cylinder 10.
  • the outer cylinder 10 is in contact with the protein solution preparation 50 at the preparation contact area 14 which is a part of the inner wall surface 13 in the outer cylinder main body 15 and the nozzle section 12.
  • the outer cylinder is a molded article of a resin containing a hydrogenated cyclic olefin ring-opening polymer and at least one of a copolymer of a cyclic olefin and a chain olefin.
  • the resin used to form the outer cylinder may contain components (other components) other than the hydrogenated cyclic olefin ring-opening polymer and the copolymer of cyclic olefin and chain olefin.
  • the hydrogenated cyclic olefin ring-opening polymer is a polymer obtained by subjecting a cyclic olefin ring-opened polymer obtained by ring-opening polymerization of a cyclic olefin as a monomer to a hydrogenation reaction.
  • the cyclic olefin which is a monomer used in the preparation of the cyclic olefin ring-opened polymer has a cyclic structure formed of carbon atoms and has a polymerizable carbon-carbon double in the cyclic structure.
  • a compound having a bond can be used.
  • examples of the cyclic olefin as a monomer include a norbornene-based monomer (a monomer containing a norbornene ring) and a monocyclic cyclic olefin monomer.
  • the “norbornene ring” contained in the norbornene-based monomer may have one or more carbon atoms interposed between carbon-carbon single bonds constituting the ring structure. As a result of the carbon atoms further forming a single bond, a new ring structure may be formed in the norbornene ring.
  • norbornene-based monomer for example, Bicyclo [2.2.1] hept-2-ene (common name: norbornene) and its derivatives (substituents on the ring; the same applies hereinafter), 5-ethylidene-bicyclo [2.2.1] hept-2 Bicyclic monomers such as -ene (common name: ethylidene norbornene) and its derivatives; Tricyclic monomers such as tricyclo [4.3.0.1 2,5 ] deca-3,7-diene (common name: dicyclopentadiene) and derivatives thereof; 7,8-tricyclo [4.3.0.1 2, 5] dec-3-ene (common name: methanolate tetrahydrofluorene and derivatives thereof, tetracyclo [7.4.0.0 2,7 .1 10 , 13 ] trideca-2,4,6,11-tetraene) and its derivatives, tetracyclo [4.4.0.1 2,5
  • dodec-3-ene (common name: tetracyclododecene) and its derivatives (eg, 8-methyl-tetracyclo [4.4.0.1 2,5 .1 7,10 ] dodeca-3) - ene, 8-ethyl - tetracyclo [4.4.0.1 2,5 .1 7,10] dodeca-3-ene), 8-ethylidene tetracyclo [4.4.0.1 2, 5.
  • 4-cyclic monomers such as 1 7,10 ] -3-dodecene and derivatives thereof; Is mentioned.
  • examples of the substituent of the above-mentioned derivative include an alkyl group such as a methyl group and an ethyl group; an alkenyl group such as a vinyl group; an alkylidene group such as an ethylidene group and a propane-2-ylidene group; Aryl group; hydroxy group; acid anhydride group; carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group;
  • Examples of the monocyclic olefin monomer include cyclic monoolefins such as cyclobutene, cyclopentene, methylcyclopentene, cyclohexene, methylcyclohexene, cycloheptene, and cyclooctene; cyclohexadiene, methylcyclohexadiene, cyclooctadiene, and methylcyclooctadiene.
  • cyclic diolefins such as phenylcyclooctadiene; and the like.
  • cyclic olefins can be used alone or in combination of two or more.
  • the cyclic olefin ring-opening polymer may be a block copolymer or a random copolymer.
  • the cyclic olefin a norbornene-based monomer is preferable, and tricyclo [4.3.0.1 2,5 ] deca-3,7-diene and its derivative, tetracyclo [4.4.0] are preferable. .1 2,5 .
  • the amount of the norbornene-based monomer used for preparing the cyclic olefin ring-opened polymer is not particularly limited, but is based on 100% by mass of the total amount of the cyclic olefin used for preparing the cyclic olefin ring-opened polymer.
  • the content is preferably 80% by mass or more, more preferably 90% by mass or more, and 100% by mass (that is, the cyclic olefin ring-opened polymer is one or two or more types of norbornene-based monomers as a monomer. Is a polymer obtained using only a monomer).
  • the method for preparing the cyclic olefin ring-opened polymer is not particularly limited, and for example, a known method of ring-opening polymerizing the above-mentioned cyclic olefin as a monomer using a metathesis polymerization catalyst can be employed. As such a method, for example, a method described in JP-A-2016-155327 can be mentioned.
  • the weight-average molecular weight (Mw) of the cyclic olefin ring-opened polymer obtained as described above is not particularly limited, but is preferably 10,000 or more, more preferably 15,000 or more, It is preferably 100,000 or less, more preferably 50,000 or less. If the weight average molecular weight of the cyclic olefin ring-opened polymer is 10,000 or more, it is possible to sufficiently secure the strength of the outer cylinder obtained by molding a resin containing a hydrogenated product of the cyclic olefin ring-opened polymer. it can.
  • the weight average molecular weight of the cyclic olefin ring-opened polymer is 100,000 or less, the moldability of the resin containing a hydrogenated product of the cyclic olefin ring-opened polymer can be sufficiently ensured.
  • the molecular weight distribution (Mw / Mn) of the cyclic olefin ring-opened polymer is not particularly limited, but is preferably 1 or more and 5 or less, more preferably 1 or more and 4 or less. When the molecular weight distribution of the cyclic olefin ring-opened polymer is within the above range, an outer cylinder having sufficient mechanical strength can be obtained.
  • the weight-average molecular weight (Mw) and number-average molecular weight (Mn) of polymers such as cyclic olefin ring-opened polymers are determined by gel permeation chromatography (GPC) using cyclohexane as an eluent. It is isoprene conversion value.
  • a hydrogenated cyclic olefin ring-opening polymer By subjecting the cyclic olefin ring-opening polymer to a hydrogenation reaction, a hydrogenated cyclic olefin ring-opening polymer can be obtained.
  • the method of hydrogenating the cyclic olefin ring-opened polymer is not particularly limited, and for example, a known method of supplying hydrogen into the reaction system in the presence of a hydrogenation catalyst can be employed. As such a method, for example, a method described in JP-A-2016-155327 can be mentioned.
  • the rate of hydrogenation (the ratio of hydrogenated main chain carbon-carbon double bonds) in the hydrogenation reaction is not particularly limited, but an outer cylinder is formed by molding a hydrogenated cyclic olefin ring-opening polymer. From the viewpoint of preventing the occurrence of burns and oxidative deterioration at the time, the content is preferably 70% or more, more preferably 80% or more, further preferably 90% or more, and particularly preferably 99% or more.
  • the “hydrogenation rate” in the hydrogenation reaction can be measured using a nuclear magnetic resonance (NMR) method.
  • NMR nuclear magnetic resonance
  • the weight average molecular weight (Mw) of the hydrogenated cyclic olefin ring-opening polymer obtained after the above-mentioned hydrogenation reaction is not particularly limited, but is preferably 10,000 or more, more preferably 15,000 or more. Preferably, it is 100,000 or less, more preferably 50,000 or less.
  • Mw weight average molecular weight of the hydrogenated cyclic olefin polymer
  • the strength of the outer cylinder obtained by molding the resin containing the hydrogenated cyclic olefin polymer is sufficiently ensured. Can be.
  • the weight average molecular weight of the hydrogenated cyclic olefin ring-opening polymer is 100,000 or less, the moldability of the resin containing the hydrogenated cyclic olefin ring-opening polymer can be sufficiently ensured.
  • the molecular weight distribution (Mw / Mn) of the hydrogenated cyclic olefin ring-opening polymer is not particularly limited, but is preferably 1 or more and 5 or less, more preferably 1 or more and 4 or less. When the molecular weight distribution of the hydrogenated cyclic olefin ring-opening polymer is in the above range, an outer cylinder having sufficient mechanical strength can be obtained.
  • Cyclic olefin and chain olefin copolymer A copolymer of a cyclic olefin and a chain olefin (hereinafter sometimes simply referred to as “copolymer”) is obtained by copolymerizing a cyclic olefin as a monomer with a linear olefin as a monomer. It is a polymer obtained by the above.
  • Cyclic olefin As the cyclic olefin which is a monomer used in the preparation of the copolymer, the same ones as described above in the section “Hydrogenated cyclic olefin-opening polymer” can be used.
  • the cyclic olefins can be used alone or in combination of two or more. Among them, bicyclo [2.2.1] hept-2-ene (common name: norbornene) and its derivative, tetracyclo [4.4.0.1 2,5 . [ 17,10 ] dodec-3-ene (common name: tetracyclododecene) and its derivatives are preferred, and bicyclo [2.2.1] hept-2-ene is more preferred.
  • the chain olefin which is a monomer used for preparing the copolymer has a chain structure formed by carbon atoms and has a polymerizable carbon-carbon double bond in the chain structure.
  • Compounds can be used.
  • compounds corresponding to cyclic olefins are not included in chain olefins.
  • examples of the chain olefin include ⁇ -olefins such as ethylene, propylene, 1-butene, 1-pentene and 1-hexene; aromatic vinyl compounds such as styrene and ⁇ -methylstyrene; 1,4-hexadiene And non-conjugated dienes such as 4-methyl-1,4-hexadiene, 5-methyl-1,4-hexadiene, and 1,7-octadiene.
  • the chain olefin can be used alone or in combination of two or more.
  • the chain olefin is preferably an ⁇ -olefin, more preferably an ⁇ -olefin having 1 to 20 carbon atoms, and still more preferably ethylene.
  • the method for preparing the copolymer is not particularly limited, and for example, a known method of addition-polymerizing the above-described cyclic olefin and chain olefin using a polymerization catalyst can be employed. As such a method, for example, a method described in JP-A-2016-155327 can be mentioned.
  • the ratio of the amount of the cyclic olefin to the amount of the chain olefin used for the preparation of the copolymer is not particularly limited, but the total amount of the amount of the cyclic olefin and the amount of the chain olefin used for the preparation of the copolymer is 100% by mass.
  • the amount of the cyclic olefin is preferably 30% by mass or more, more preferably 50% by mass or more, still more preferably 70% by mass or more, and preferably 99% by mass or less. It is more preferably at most 97% by mass, further preferably at most 95% by mass.
  • the copolymer of a cyclic olefin and a chain olefin may be a block copolymer or a random copolymer.
  • the weight average molecular weight (Mw) of the copolymer of cyclic olefin and chain olefin is not particularly limited, but is preferably 20,000 or more, more preferably 25,000 or more, and more preferably 100,000. Or less, more preferably 50,000 or less.
  • Mw weight average molecular weight
  • the weight average molecular weight of the copolymer is 20,000 or more, the strength of the outer cylinder obtained by molding the resin containing the copolymer can be sufficiently ensured.
  • the weight average molecular weight of the copolymer is 100,000 or less, the moldability of the resin containing the copolymer can be sufficiently ensured.
  • the molecular weight distribution (Mw / Mn) of the copolymer is not particularly limited, but is preferably 1 or more and 5 or less, more preferably 1 or more and 4 or less. When the molecular weight distribution of the copolymer is in the above range, an outer cylinder having sufficient mechanical strength can be obtained.
  • the resin used for forming the outer cylinder may include at least one of a hydrogenated cyclic olefin ring-opening polymer and a copolymer of a cyclic olefin and a chain olefin. It is preferable to include a hydrogenated cyclic polymer.
  • Other components that can be included in the resin used to form the outer cylinder include polymer components other than the above-described polymers (such as thermoplastic elastomers) and known additives.
  • the known additives include, for example, antioxidants, ultraviolet absorbers, light stabilizers, near infrared absorbers, plasticizers, antistatic agents, and acid scavengers described in JP-A-2016-155327. And the like. The content of these other components in the resin can be appropriately determined according to the purpose of adding the components.
  • the amount used is 100 parts by mass of the total amount of the hydrogenated cyclic olefin ring-opening polymer and the copolymer of the cyclic olefin and the chain olefin (when each is used alone). Is preferably from 0.05 to 0.5 part by mass, with any amount being 100 parts by mass.
  • the mixing method at the time of obtaining the resin containing the above-mentioned polymer and optionally other components is not particularly limited, and examples thereof include a single-screw extruder, a twin-screw extruder, a Banbury mixer, a kneader, and a feeder ruder. Can be performed using a known melt kneader. After mixing, the mixture can be extruded into a rod shape and cut into an appropriate length with a strand cutter to form a pellet according to a conventional method.
  • the method of molding the resin containing the above-described components to obtain the outer cylinder is not particularly limited, and for example, using the method described in the section of “Method for Manufacturing Prefilled Syringe”, including a nozzle portion at the distal end portion
  • the outer cylinder can be formed.
  • the outer cylinder obtained as described above needs to have a preparation contact region having a water contact angle of 90 ° or more on the inner wall surface.
  • the water contact angle of the preparation contact area is less than 90 °, aggregation of the protein in the protein solution preparation cannot be suppressed when the prefilled syringe provided with the outer cylinder is stored for a long time.
  • the water contact angle of the preparation contact region is preferably 91 ° or more, more preferably 92 ° or more, and more preferably 93 ° or more. It is even more preferred.
  • the upper limit of the water contact angle in the preparation contact region is not particularly limited, but is usually 110 ° or less.
  • the water contact angle in the formulation contact region can be adjusted by changing the type of polymer and additives contained in the resin used to form the outer cylinder and the method of manufacturing the outer cylinder. For example, by using a hydrophobic polymer (having no hydrophilic group or the like) as a polymer or an additive, the value of the water contact angle in the preparation contact region can be improved. Further, for example, prior to the molding of the resin, the value of the water contact angle in the preparation contact area can be improved by performing the predrying described in the section of “Method of Manufacturing Prefilled Syringe” described below.
  • the sealing member provided in the prefilled syringe of the present invention is not particularly limited as long as it can prevent leakage of the protein solution preparation from the distal end portion of the outer cylinder, and a known one such as a cap or an injection needle can be used.
  • the prefilled syringe 1 of FIG. 1 includes a cap that fits with the nozzle 12 of the outer cylinder 10 as the sealing member 20.
  • the material for forming the sealing member is not particularly limited.
  • a known resin described in Utility Model Registration No. 3150720 can be used.
  • the gasket provided in the prefilled syringe of the present invention is not particularly limited as long as it can seal the protein solution preparation in the outer cylinder.
  • the gasket preferably has at least an outer peripheral portion made of an elastic material.
  • the gasket has, for example, a core (not shown) made of a rigid material. A configuration in which a rigid material is arranged so as to cover the surface.
  • the material for forming the gasket is not particularly limited. For example, elastic rubber and synthetic resin described in Japanese Patent No. 5444835 can be used.
  • the pusher included in the prefilled syringe of the present invention is a member that is connected to the above-described gasket and can move the gasket in the above-described outer cylinder in the longitudinal direction.
  • the presser 40 includes a finger contact portion 41 at an end opposite to the gasket 30, and the presser 40 is pressed by pressing the finger contact portion 41 with a finger or the like. Move operation. Since the gasket 30 also moves in conjunction with the movement of the pusher 40, the protein solution preparation 50 can be discharged from the nozzle 12 of the outer cylinder 10 to the outside.
  • the material for forming the pusher is not particularly limited, and for example, a resin described in Japanese Patent No. 5444835 can be used.
  • the above-mentioned prefilled syringe of the present invention can be suitably manufactured by the manufacturing method of the prefilled syringe of the present invention, for example.
  • the method for manufacturing a prefilled syringe of the present invention includes an outer cylinder having a nozzle portion at a distal end portion, a sealing member for sealing the nozzle portion, a gasket slidably housed in the outer cylinder, and a gasket. And a pusher for moving the gasket in the longitudinal direction of the outer cylinder to produce a prefilled syringe in which a protein solution preparation is filled inside a syringe.
  • the method for producing a prefilled syringe of the present invention includes at least a step of filling a protein solution preparation into an outer cylinder to obtain a prefilled syringe filled with the protein solution preparation (filling step).
  • the outer cylinder is a resin molded article containing a hydrogenated cyclic olefin ring-opening polymer and / or a copolymer of a cyclic olefin and a chain olefin, and has a water contact angle of 90 ° on a part of the inner wall surface.
  • a space defined by the above-mentioned region, the sealing member, and the gasket is filled with a protein solution preparation having a nonionic surfactant concentration of 0 mg / mL or more and 0.01 mg / mL or less. It is characterized by doing.
  • the pre-filled syringe obtained by filling a protein solution preparation having a nonionic surfactant concentration of 0 mg / mL or more and 0.01 mg / mL or less in the above-mentioned filling step is the reason described above in the section of “Pre-filled syringe”. For the same reason as described above, even when stored for a long time, aggregation of proteins in the protein solution preparation can be suppressed.
  • nozzle part In the following description, “nozzle part”, “outer cylinder”, “hydrogenated cyclic olefin ring-opening polymer”, “copolymer of cyclic olefin and chain olefin”, “resin”, “sealing member” , “Gasket”, “presser”, “protein solution preparation” and the like are the same as those described above in the section of “Prefilled syringe”.
  • Specific examples and preferred examples of the “sealing member”, “gasket”, “presser”, and “protein solution preparation” are the “nozzle part”, “outer cylinder”, “annular” in the above-described prefilled syringe of the present invention.
  • a protein solution preparation is injected into the outer cylinder, and a nonionic interface is formed in a region defined by the inner wall surface of the outer cylinder where the water contact angle is 90 ° or more (formulation contact region), the sealing member, and the gasket.
  • the method for filling the protein solution preparation having an active agent concentration within a predetermined range is not particularly limited, and includes a known method, for example, a method described in JP-A-2012-29918.
  • the filling step is preferably performed under sterilization.
  • the method for producing a prefilled syringe of the present invention can optionally include a step other than the above-described filling step (another step).
  • a step other than the above-described filling step another step.
  • the manufacturing method of the prefilled syringe of the present invention prior to the filling step described above, a step of pre-drying the resin as a molding material (pre-drying step), and forming the resin after pre-drying, It is preferable to include a step of forming the outer cylinder (forming step).
  • Preliminary drying step By drying the resin used to form the outer cylinder prior to molding, the water contact angle on the outer cylinder surface (particularly, the formulation contact area on the inner wall surface) is improved, and the aggregation of proteins in the protein solution formulation is reduced. It can be suppressed sufficiently.
  • the reason why the water contact angle on the outer cylinder surface obtained after molding can be improved by drying the resin before molding is not clear, but the oxygen concentration in the resin can be reduced by drying. Therefore, it is speculated that the surface of the outer cylinder is prevented from being oxidized by the heat at the time of molding and becoming hydrophilic.
  • the shape of the resin at the time of preliminary drying is not particularly limited, and may be any shape such as a sheet shape and a pellet shape. However, from the viewpoint of drying efficiency and ease of molding, the shape of the resin is preferably a pellet shape. Is preferred.
  • the oxygen concentration in the resin after preliminary drying is preferably 10 ppm by mass or less, more preferably 5 ppm by mass or less, and even more preferably 4 ppm by mass or less. If the oxygen concentration in the resin after the preliminary drying is 10 mass ppm or less, the value of the water contact angle of the formulation contact region of the outer cylinder formed from the resin can be improved, and the prefilled syringe provided with the outer cylinder In the above, protein aggregation in the protein solution preparation can be sufficiently suppressed.
  • the preliminary drying be performed in an inert gas atmosphere.
  • an inert gas atmosphere By performing the pre-drying under an inert gas atmosphere, it is possible to prevent the oxidation of the resin by external oxygen while efficiently removing oxygen from the resin, and as a result, in a prefilled syringe having an outer cylinder obtained.
  • aggregation of proteins in a protein solution preparation can be sufficiently suppressed.
  • the inert gas helium, argon, nitrogen, neon, krypton, and a mixture thereof can be used.
  • the drying temperature is preferably 80 ° C. or higher, more preferably 90 ° C. or higher, even more preferably 100 ° C. or higher, and preferably 120 ° C. or lower. , 110 ° C. or lower.
  • the drying temperature of the predrying is 80 ° C. or higher, oxygen in the resin can be efficiently removed.
  • the drying temperature of the preliminary drying is 120 ° C. or lower, it is possible to prevent the resin from being cured prior to molding.
  • the drying time is preferably 1 hour or more, more preferably 2 hours or more, still more preferably 4 hours or more, and preferably 24 hours or less, and 12 hours. It is more preferred that: If the drying time of the pre-drying is 1 hour or more, oxygen in the resin can be efficiently removed, and as a result, the aggregation of the protein in the protein solution preparation can be sufficiently achieved in the obtained prefilled syringe having the outer cylinder. Can be suppressed. On the other hand, if the drying time of the preliminary drying is 24 hours or less, it is possible to prevent the resin from being oxidized and deteriorated prior to molding.
  • the method of molding the above-mentioned resin after pre-drying into an outer cylinder having a desired shape is not particularly limited, and known molding methods such as an injection molding method, an injection blow molding method (a cold parison method), and a thermoforming method are exemplified. Can be Among these, the injection molding method is preferable because the target outer cylinder can be efficiently manufactured.
  • a resin is put into a hopper of an injection molding machine, plasticized by heating in a cylinder, and then molten resin (plasticized resin). Is injected into the mold from the injection port. Then, the outer cylinder is formed by cooling and solidifying the molten resin in the mold.
  • the cylinder temperature at the time of plasticizing the resin is preferably 200 ° C. or more and 400 ° C. or less, more preferably 200 ° C. or more and 350 ° C. or less, and further preferably 250 ° C. or more and 310 ° C. or less. preferable.
  • the cylinder temperature is 200 ° C. or higher, the fluidity of the molten resin is ensured, and there is no sink or distortion in the outer cylinder.
  • the cylinder temperature is 400 ° C. or less, occurrence of silver streaks due to thermal decomposition of the molding material and yellowing of the outer cylinder can be suppressed.
  • injection speed at the time of injecting the molten resin from the cylinder into the mold is preferably 1 cm 3 / sec or more 1,000 cm 3 / sec or less. When the injection speed is in this range, it becomes easy to obtain an outer cylinder having an excellent appearance.
  • the injection pressure when injecting the molten resin from the cylinder to the mold is not particularly limited, and may be appropriately set in consideration of the type of the mold, the fluidity of the molten resin, and the like, but is usually 30 MPa or more. It is 250 MPa or less.
  • the mold temperature is usually lower than the glass transition temperature (Tg) of the polymer (hydrogenated cyclic olefin ring-opening polymer and / or copolymer of cyclic olefin and chain olefin) in the resin.
  • Tg glass transition temperature
  • the temperature is preferably 5 ° C. to 50 ° C. lower than Tg, more preferably 5 ° C. to 30 ° C. lower than Tg. When the mold temperature is within this range, an outer cylinder with less distortion can be easily obtained.
  • the method for producing a prefilled syringe of the present invention includes, in addition to the above-described preliminary drying step and molding step, other steps, for example, a step of sterilizing an outer cylinder, a gasket, and a sealing member before a filling step. You can also.
  • ⁇ Water contact angle> The outer cylinder is cut with a nipper to cut out the preparation contact area, and a curve fitting method is used for any 10 points in the preparation contact area using a cooperating contact angle meter (manufactured by Kyowa Interface Science Co., Ltd., product name “Drop Master 300”). The static contact angles were measured, and the average value was defined as the water contact angle in the formulation contact area.
  • ⁇ Inhibition of protein aggregation> The prefilled syringe was allowed to stand at 4 ° C. for one week in the dark. After one week of standing, the protein solution preparation in the prefilled syringe was recovered by applying pressure to a pusher connected to a gasket and extruding it from a nozzle.
  • the number of aggregates having a particle diameter of 1 ⁇ m or more contained in the recovered protein solution preparation was visually counted using FlowCam8100 (Fluid Imaging Technologies, Scarborough, ME).
  • the sample volume was 0.15 mL, and analysis was performed at a flow rate of 0.05 mL / min.
  • Visual Spreadsheet software (Fluid Imaging Technologies) was used. The same operation was performed four times in total. Then, the number of aggregates per unit volume (units / mL) was calculated for each run, and the average value thereof was taken as the aggregate concentration (units / mL) after storage. It can be said that the smaller the value of the aggregate concentration after storage is, the more the aggregation of the protein in the protein solution preparation is suppressed when the prefilled syringe is stored for a long time.
  • Example 1 Preparation of protein solution preparation> The purified Humira (adalimumab) was adjusted to a concentration of 0.1 mg / mL using phosphate buffered saline (pH: 7.0, NaCl: 200 mM, phosphoric acid: 100 mM), and the protein solution formulation was prepared. Obtained.
  • the hydride was extruded in a molten state from an extruder into a strand, cooled, and pelletized to obtain pellets.
  • Mw of the pelletized cyclic olefin ring-opening polymer hydrogenated product (hydride A) is 33,000, molecular weight distribution (Mw / Mn) is 2.4, hydrogenation rate is 99.8%, and Tg is 136. ° C.
  • Example 2 A protein solution preparation was prepared in the same manner as in Example 1 except that the drying time of the preliminary drying was changed to 3 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared and various evaluations were performed. . Table 1 shows the results.
  • Example 3 In preparing the protein solution preparation, a protein solution preparation was prepared in the same manner as in Example 1, except that polysorbate 80 as a nonionic surfactant was added so as to have a concentration of 0.01 mg / mL. In addition, an outer cylinder and a prefilled syringe were prepared and various evaluations were made. Table 1 shows the results.
  • Example 4 A protein solution preparation was prepared in the same manner as in Example 1 except that the drying time of the preliminary drying was changed to 1.5 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared. went. Table 1 shows the results.
  • Example 5 Except for using a copolymer of cyclic olefin and chain olefin (copolymer B) prepared as described below in place of hydrogenated cyclic olefin ring-opening polymer (hydride A) when producing the outer cylinder.
  • copolymer B a copolymer of cyclic olefin and chain olefin
  • hydrolymer A hydrogenated cyclic olefin ring-opening polymer
  • the polymer liquid phase purified and separated was brought into contact with a three-fold amount of acetone under vigorous stirring to precipitate a copolymer, and then a solid part (copolymer) was collected by filtration and sufficiently washed with acetone. . Further, in order to extract unreacted monomer, this solid portion was charged into acetone so as to be 40 kg / m 3, and then an extraction operation was performed at 60 ° C. for 2 hours. After the extraction treatment, the solid portion was collected by filtration, and dried at 130 ° C. and 350 mmHg for 12 hours under a nitrogen stream to obtain an ethylene / norbornene copolymer (copolymer B).
  • the ethylene / norbornene copolymer (copolymer B) was pelletized in the same manner as in the hydride A of Production Example 1.
  • the pelletized ethylene / norbornene copolymer (copolymer B) had a weight average molecular weight (Mw) of 96,000, a molecular weight distribution (Mw / Mn) of 2.4, and a Tg of 138 ° C.
  • Example 6 A protein solution preparation was prepared in the same manner as in Example 5, except that the drying time of the preliminary drying was changed to 3 hours, and an outer cylinder and a prefilled syringe were prepared. . Table 1 shows the results.
  • Example 7 In preparing the protein solution preparation, a protein solution preparation was prepared in the same manner as in Example 5, except that polysorbate 80 as a nonionic surfactant was added so as to have a concentration of 0.01 mg / mL. In addition, an outer cylinder and a prefilled syringe were prepared and various evaluations were made. Table 1 shows the results.
  • Example 8 A protein solution preparation was prepared in the same manner as in Example 5 except that the drying time of the preliminary drying was changed to 1.5 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared. went. Table 1 shows the results.
  • Example 9 An outer cylinder and a prefilled syringe were prepared and various evaluations were performed in the same manner as in Example 1 except that the protein solution preparation prepared as described below was used. Table 1 shows the results. ⁇ Preparation of protein solution preparation> The purified remicade (infliximab) was adjusted to a concentration of 0.1 mg / mL using phosphate buffered saline (pH: 7.0, NaCl: 200 mM, phosphoric acid: 100 mM), and the protein solution preparation was prepared. Obtained.
  • Example 10 A protein solution preparation was prepared in the same manner as in Example 9, except that the drying time of the preliminary drying was changed to 3 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared and various evaluations were performed. . Table 1 shows the results.
  • Example 11 In preparing the protein solution preparation, a protein solution preparation was prepared in the same manner as in Example 9, except that polysorbate 80 as a nonionic surfactant was added so as to have a concentration of 0.01 mg / mL. In addition, an outer cylinder and a prefilled syringe were prepared and various evaluations were made. Table 1 shows the results.
  • Example 12 A protein solution preparation was prepared in the same manner as in Example 9 except that the drying time of the preliminary drying was changed to 1.5 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared. went. Table 1 shows the results.
  • Example 13 When producing the outer cylinder, a cyclic olefin-chain olefin copolymer (copolymer B) prepared in the same manner as in Example 5 was used instead of the cyclic olefin ring-opening polymer hydrogenated product (hydride A). A protein solution preparation was prepared, an outer cylinder and a prefilled syringe were prepared, and various evaluations were performed in the same manner as in Example 9 except for using the same. Table 2 shows the results.
  • Example 14 A protein solution preparation was prepared in the same manner as in Example 13, except that the drying time of the preliminary drying was changed to 3 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared and various evaluations were performed. . Table 2 shows the results.
  • Example 15 In preparing the protein solution preparation, a protein solution preparation was prepared in the same manner as in Example 13, except that polysorbate 80 as a nonionic surfactant was added so as to have a concentration of 0.01 mg / mL. In addition, an outer cylinder and a prefilled syringe were prepared and various evaluations were made. Table 2 shows the results.
  • Example 16 A protein solution preparation was prepared in the same manner as in Example 13 except that the drying time of the preliminary drying was changed to 1.5 hours when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared. went. Table 2 shows the results.
  • Example 17 An outer cylinder and a prefilled syringe were prepared and various evaluations were performed in the same manner as in Example 1 except that the protein solution preparation prepared as described below was used. Table 2 shows the results.
  • Example 18 An outer cylinder and a prefilled syringe were prepared and various evaluations were performed in the same manner as in Example 1 except that the protein solution preparation prepared as described below was used. Table 2 shows the results.
  • ⁇ Preparation of protein solution preparation> A purified Humira (adalimumab) was prepared by adding NaCl to an acetate buffer (pH: 5.0, acetic acid: 100 mM) and adjusting the concentration to 20 mM (NaCl concentration) with a concentration of 0.1 mg / mL. To obtain a protein solution preparation.
  • Example 19 An outer cylinder and a prefilled syringe were prepared and various evaluations were performed in the same manner as in Example 1 except that the protein solution preparation prepared as described below was used. Table 2 shows the results.
  • ⁇ Preparation of protein solution preparation> A purified Humira (adalimumab) was prepared by adding NaCl to an acetate buffer (pH: 5.0, acetic acid: 100 mM) and adjusting the concentration to 200 mM (NaCl concentration) at a concentration of 0.1 mg / mL. To obtain a protein solution preparation.
  • Example 20 An outer cylinder and a prefilled syringe were prepared and various evaluations were performed in the same manner as in Example 1 except that the protein solution preparation prepared as described below was used. Table 2 shows the results.
  • Example 21 An outer cylinder and a prefilled syringe were prepared and various evaluations were performed in the same manner as in Example 1 except that the protein solution preparation prepared as described below was used. Table 2 shows the results. ⁇ Preparation of protein solution preparation> The purified Humira (adalimumab) was adjusted to a concentration of 0.1 mg / mL using phosphate buffered saline (pH: 6.0, NaCl: 200 mM, phosphoric acid: 100 mM), and the protein solution formulation was prepared. Obtained.
  • Example 22 When producing the outer cylinder, a cyclic olefin ring-opening polymer hydrogenated product (hydride C) prepared as described below was used instead of the cyclic olefin ring-opening polymer hydrogenated product (hydride A). In the same manner as in Example 1, a protein solution preparation was prepared, an outer cylinder and a prefilled syringe were prepared, and various evaluations were made. Table 2 shows the results.
  • Diatomaceous earth was spread over the wire mesh of a filter equipped with a stainless steel wire mesh as a filter aid, and the hydrogenation reaction solution was filtered to remove the catalyst.
  • the filtered reaction solution was poured into 3000 parts of isopropyl alcohol with stirring to precipitate a hydrogenated product, which was collected by filtration. Further, the obtained hydrogenated product was washed with 500 parts of acetone, and then dried for 48 hours in a reduced pressure drier set at 100 ° C. or lower at 1 torr or less, and a cyclic olefin ring-opened polymer hydrogenated product (hydride C) 190 Got a part.
  • the hydrogenated cyclic olefin ring-opening polymer (hydride C) was pelletized in the same manner as the hydride A of Production Example 1.
  • Example 23 In preparing the protein solution preparation, a protein solution preparation was prepared in the same manner as in Example 22 except that polysorbate 80 as a nonionic surfactant was added so as to have a concentration of 0.01 mg / mL. In addition, an outer cylinder and a prefilled syringe were prepared and various evaluations were made. Table 2 shows the results.
  • Example 24 In obtaining resin pellets, 0.1 part of an aromatic vinyl / conjugated diene block copolymer (Tufftec (registered trademark) H1043, manufactured by Asahi Kasei Chemicals Corporation) and an aromatic vinyl / conjugated diene block are used as stabilizers (thermoplastic elastomer).
  • a protein solution preparation was prepared in the same manner as in Example 1, except that 0.1 part of a polymer (Tuftec (registered trademark) H1051 manufactured by Asahi Kasei Chemicals Corporation) was additionally added, and an outer cylinder and a prefilled syringe were prepared. And various evaluations. The results are shown in Table 2.
  • Example 1 A protein solution preparation was prepared in the same manner as in Example 1 except that predrying was not performed when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared and various evaluations were performed. Table 3 shows the results.
  • Example 2 A protein solution preparation was prepared in the same manner as in Example 5, except that predrying was not performed when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared and various evaluations were performed. Table 3 shows the results.
  • Example 3 A protein solution preparation was prepared, a prefilled syringe was prepared, and various evaluations were performed in the same manner as in Example 1 except that a glass outer cylinder was used as the outer cylinder. Table 3 shows the results.
  • Example 4 A protein solution preparation was prepared in the same manner as in Example 3 except that a glass outer cylinder was used as the outer cylinder, a prefilled syringe was prepared, and various evaluations were performed. Table 3 shows the results.
  • Example 5 A protein solution preparation was prepared in the same manner as in Example 9 except that predrying was not performed when preparing the outer cylinder, and an outer cylinder and a prefilled syringe were prepared and various evaluations were performed. Table 3 shows the results.
  • Example 6 A protein solution preparation was prepared in the same manner as in Example 13, except that predrying was not performed when the outer cylinder was prepared, and an outer cylinder and a prefilled syringe were prepared, and various evaluations were made. Table 3 shows the results.
  • Example 7 A protein solution preparation was prepared in the same manner as in Example 9 except that a glass outer cylinder was used as the outer cylinder, a prefilled syringe was prepared, and various evaluations were performed. Table 3 shows the results.
  • Example 8 A protein solution preparation was prepared in the same manner as in Example 11, except that a glass outer cylinder was used as the outer cylinder, and a prefilled syringe was prepared, and various evaluations were performed. Table 3 shows the results.
  • the protein solution preparation was formed of a resin containing a hydrogenated cyclic olefin ring-opening polymer and / or a copolymer of a cyclic olefin and a chain olefin, and had a water contact angle of 90 in the preparation contact area.
  • the prefilled syringes of Examples 1 to 24 obtained by filling an outer cylinder having a temperature of not less than 0 ° C. were obtained when the concentration of the nonionic surfactant in the protein solution preparation was as low as 0 mg / mL to 0.01 mg / mL. Even if there is, it is understood that aggregation of the protein after long-term storage can be suppressed.
  • Examples 5 to 8 and Comparative Example 2 were compared, they are common to the protein (adalimumab) in the protein solution preparation and the material (copolymer B) used to form the outer cylinder. Since the water contact angle in the preparation contact area is less than 90 °, the value of the aggregate concentration after storage is significantly higher than in Examples 5 to 8. Further, comparing Examples 9 to 12 with Comparative Example 5, they are common to the protein (infliximab) in the protein solution formulation and the material (hydride A) used to form the outer cylinder.
  • Example 13 to 16 and Comparative Example 6 are compared, they are common in the protein (infliximab) in the protein solution preparation and the material (copolymer B) used to form the outer cylinder. Since the water contact angle of the preparation contact area is less than 90 °, the value of the aggregate concentration after storage is much higher than in Examples 13 to 16. Further, Table 3 shows that the pre-filled syringes of Comparative Examples 3, 4, 7, and 8 using the outer cylinder formed of glass cannot suppress protein aggregation after long-term storage.
  • a prefilled syringe capable of suppressing protein aggregation after long-term storage even when a protein solution preparation having a low concentration of a nonionic surfactant is filled. Further, according to the present invention, there is provided a method for producing a prefilled syringe capable of suppressing protein aggregation after long-term storage, even when a protein solution preparation having a low concentration of a nonionic surfactant is filled. be able to.

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Abstract

L'objectif de la présente invention est de fournir une seringue pré-remplie dans laquelle l'agrégation de protéine après stockage à long terme peut être supprimée, même lorsqu'elle est remplie avec une formulation de solution protéique, la concentration d'un tensioactif non ionique étant faible. Cette seringue pré-remplie comprend : un cylindre externe comprenant une résine contenant un produit polymère à cycle ouvert hydrogéné d'une oléfine cyclique et/ou d'un copolymère d'une oléfine cyclique et d'une oléfine linéaire; un élément d'étanchéité scellant une section de buse du cylindre externe; un joint d'étanchéité logé à l'intérieur du cylindre externe; et un piston effectuant une opération de déplacement du joint d'étanchéité. La formulation de solution protéique est contenue dans un espace délimité par le joint d'étanchéité, l'élément d'étanchéité et une région qui est une partie de la surface de paroi interne de cylindre externe. L'angle de contact avec l'eau dans la région qui est une partie de la surface de paroi interne est de 90° ou plus. La concentration du tensioactif non ionique dans la formulation de solution protéique est comprise entre 0 mg/mL et 0,01 mg/mL inclus.
PCT/JP2019/029092 2018-07-31 2019-07-24 Seringue pré-remplie et procédé de production de seringue pré-remplie WO2020026926A1 (fr)

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US17/261,568 US20210260297A1 (en) 2018-07-31 2019-07-24 Pre-filled syringe and method of producing pre-filled syringe
EP19844828.4A EP3831429A4 (fr) 2018-07-31 2019-07-24 Seringue pré-remplie et procédé de production de seringue pré-remplie
CN201980048561.XA CN112469456B (zh) 2018-07-31 2019-07-24 预充式注射器和预充式注射器的制造方法
JP2020533462A JP7484715B2 (ja) 2018-07-31 2019-07-24 プレフィルドシリンジおよびプレフィルドシリンジの製造方法

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JP2018143855 2018-07-31
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JP3150720U (ja) 2009-03-12 2009-05-28 テルモ株式会社 プレフィルドシリンジ
JP2012029918A (ja) 2010-07-30 2012-02-16 Terumo Corp ガスケット、プレフィルドシリンジ、及び打栓方法
JP5444835B2 (ja) 2009-05-20 2014-03-19 大日本印刷株式会社 プレフィルドシリンジ用注射器およびプレフィルドシリンジ
WO2016051962A1 (fr) * 2014-10-02 2016-04-07 テルモ株式会社 Récipient médical pour recevoir une préparation de solution de protéine à l'intérieur de ce dernier
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JP3150720U (ja) 2009-03-12 2009-05-28 テルモ株式会社 プレフィルドシリンジ
JP5444835B2 (ja) 2009-05-20 2014-03-19 大日本印刷株式会社 プレフィルドシリンジ用注射器およびプレフィルドシリンジ
JP2012029918A (ja) 2010-07-30 2012-02-16 Terumo Corp ガスケット、プレフィルドシリンジ、及び打栓方法
JP2016059635A (ja) * 2014-09-18 2016-04-25 キョーラク株式会社 プレフィルドシリンジ
WO2016051962A1 (fr) * 2014-10-02 2016-04-07 テルモ株式会社 Récipient médical pour recevoir une préparation de solution de protéine à l'intérieur de ce dernier
JP2016155327A (ja) 2015-02-25 2016-09-01 日本ゼオン株式会社 樹脂製容器の製造方法および樹脂製容器
WO2017087798A1 (fr) * 2015-11-18 2017-05-26 Formycon Ag Conditionnement pharmaceutique prérempli comprenant une formulation liquide d'un antagoniste du vegf
JP2018070784A (ja) * 2016-10-31 2018-05-10 日本ゼオン株式会社 樹脂組成物及び樹脂成形体

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See also references of EP3831429A4

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EP3831429A4 (fr) 2021-12-29
US20210260297A1 (en) 2021-08-26
CN112469456A (zh) 2021-03-09
JPWO2020026926A1 (ja) 2021-08-12
CN112469456B (zh) 2023-02-28

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